Small vessel disease (SVD) is thought to be among the most prevalent disorders of the central nervous system and contributes a key mechanistic role in the syndrome of vascular cognitive impairment and dementia (VCID). A major challenge in the investigation of cerebral SVD is that small vessel integrity cannot be visualized in vivo. Instead, MRI lesions, most notably white matter hyperintensities, currently provide the most widely accepted biomarker of SVD. However, MRI white matter lesions represent downstream effects of SVD and further are not specific to ischemic brain injury. Noninvasive imaging strategies capable of detecting mechanistically- specific changes in small vessel structure or function would improve the identification and quantification of small vessel contributions to cognitive impairment and dementia and serve as biomarkers for monitoring the effects of therapeutic interventions in clinical trials. As we show in preliminary data, recent developments in the spatial resolution and sensitivity of arterial spin labeled (ASL) perfusion MRI now allow noninvasive quantification of cerebral blood flow (CBF) from the periventricular white matter (PVWM), which is supplied by the terminal distributions of long arterioles much less than 100 microns in diameter. PVWM-CBF accordingly represents a promising biomarker of small vessel perfusion, allowing quantification of small vessel functional integrity without spatially resolving individual arteries. Concomitantly, emerging optical methods such as optical coherence tomographic angiography (OCTA) also allow small vessels and even capillaries to be rapidly noninvasively imaged in the human retina using relatively inexpensive and increasingly widely available instrumentation. Both biomarkers hold the potential to detect mechanistically specific changes in small vessel structural or functional integrity prior to the development of brain lesions been formally established. However, while retina has been described as a ?window? to the brain, the relationship between OCTA measures of retina and brain structure and function has yet to be adequately tested. The overall goal of this proposal is to validate PVWM CBF and OCTA-derived microvascular density as bona fide biomarkers of human small vessel structure for use in clinical research. We will investigate the biological and technical determinants of PVWM CBF and OCTA-derived microvascular density, associate changes in retinal microvasculature with brain WML and perfusion, and preliminarily show their predictive value in SVD by correlating baseline measures with longitudinal changes in healthy and clinical cohorts. A multidisciplinary team of investigators with expertise in neuroimaging, retinal imaging, cerebral blood flow physiology, cerebrovascular disorders, aging, and dementia will collaborate to carry out this work.